Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

Carlos W. Gantner; Isabelle R. de Luzy; Jessica A. Kauhausen; Niamh Moriarty; Jonathan C. Niclis; Christopher R. Bye; Vanessa Penna; Cameron P.J. Hunt; Charlotte M. Ermine; Colin W. Pouton; Deniz Kirik; Lachlan H. Thompson; Clare L. Parish

doi:10.1016/j.stem.2020.01.010

Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

Carlos W. Gantner, Isabelle R. de Luzy, Jessica A. Kauhausen, Niamh Moriarty, Jonathan C. Niclis, Christopher R. Bye, Vanessa Penna, Cameron P.J. Hunt, Charlotte M. Ermine, Colin W. Pouton, Deniz Kirik, Lachlan H. Thompson, Clare L. Parish

Drug Delivery Disposition & Dynamics

Research output: Contribution to journal › Article › Research › peer-review

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Abstract

Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

Original language	English
Pages (from-to)	511-526
Number of pages	21
Journal	Cell Stem Cell
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2020.01.010
Publication status	Published - 2 Apr 2020

Keywords

dopamine
GDNF
glial cell line-derived neurotrophic factor
graft integration
human embryonic stem cells
LMX1A
neural plasticity
Parkinson’s disease
PITX3
transplantation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.stem.2020.01.010

Cite this

Gantner, C. W., de Luzy, I. R., Kauhausen, J. A., Moriarty, N., Niclis, J. C., Bye, C. R., Penna, V., Hunt, C. P. J., Ermine, C. M., Pouton, C. W., Kirik, D., Thompson, L. H., & Parish, C. L. (2020). Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease. Cell Stem Cell, 26(4), 511-526. https://doi.org/10.1016/j.stem.2020.01.010

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abstract = "Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.",

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AB - Dopaminergic neurons (DAns), generated from human pluripotent stem cells (hPSCs), are capable of functionally integrating following transplantation and have recently advanced to clinical trials for Parkinson's disease (PD). However, pre-clinical studies have highlighted the low proportion of DAns within hPSC-derived grafts and their inferior plasticity compared to fetal tissue. Here, we examined whether delivery of a developmentally critical protein, glial cell line-derived neurotrophic factor (GDNF), could improve graft outcomes. We tracked the response of DAns implanted into either a GDNF-rich environment or after a delay in exposure. Early GDNF promoted survival and plasticity of non-DAns, leading to enhanced motor recovery in PD rats. Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, and DA metabolism. Transcriptional profiling revealed a role for mitogen-activated protein kinase (MAPK)-signaling downstream of GDNF. Collectively, these results demonstrate the potential of neurotrophic gene therapy strategies to improve hPSC graft outcomes.

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Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Standardising protocols for the differentiation and integration of human pluripotent stem cell-derived neural transplants in Parkinson's disease

Cite this

Viral Delivery of GDNF Promotes Functional Integration of Human Stem Cell Grafts in Parkinson's Disease

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Standardising protocols for the differentiation and integration of human pluripotent stem cell-derived neural transplants in Parkinson's disease

Cite this